Maturation of cells of the oligodendrocyte (OLG) lineage is characterized by extensive changes in cellular morphology. These changes are to a large extent driven by changes in the actin cytoskeleton. Interestingly, within lesions seen in the central nervous system (CNS) of patients suffering from the major human demyelinating disease Multiple Sclerosis, OLG differentiation appears blocked and actin cytoskeleton regulatory mechanisms misregulated. Thus and as an approach toward a better understanding on how to achieve myelin repair under pathological conditions, the long-term goal of the studies proposed in this grant application is to gain insight into the role of actin cytoskeleton regulator mechanisms in the overall control of OLG differentiation and CNS myelination. Our recently published and preliminary studies identified calcium/calmodulin-dependent protein kinase Ii (CaMKII) as a good candidate for a factor that can modulate kinetic stability versus dynamic remodeling of the OLG's actin cytoskeleton and thereby regulate OLG maturation and CNS myelination. Based on our data we propose as our central hypothesis that CaMKII acts in differentiating OLGs as an actin cytoskeleton regulatory protein critically involved in controlling the morphological aspects of OLG maturation and myelination. To address this hypothesis we will complete the following two specific aims: 1) we will characterize in vivo the role of OLGderived CaMKII in regulating developmental myelination and the myelin-associated actin cytoskeleton and 2) we will characterize in vitro the role of CaMKII and its actin binding/ stabilizing domain in regulating the maturation of differentiating OLG and the OLG's actin cytoskeleton. Taken together, the experiments to be completed as part of this grant proposal are anticipated to build the basis for continuing studies in which to further assess the role of th CaMKII-actin cytoskeleton axis in CNS myelination as well as remyelination and to thus contribute to a better understanding on how to stimulate CNS repair under pathological demyelinating conditions.